Disclosure. Learning Objectives 9/20/2012

John Papadopoulos, B.S., Pharm.D., FCCM, BCNSP Associate Professor of Pharmacy Practice Arnold & Marie Schwartz College of Pharmacy

and

Director of Pharmacotherapy Critical Care Pharmacist Pharmacy Residency Program Director Clinical Assistant Professor of Medicine New York University Langone Medical Center



Disclosure



Describe resuscitation goals for the management of shock

Explain the use of fluids to meet defined goals of resuscitation

Compare the various vasoactive agents that may be utilized in the management of shock

Demonstrate application of obtained knowledge



Sepsisderived from Greek language Synonymous with bad smell or putrefaction Shockderived from the French language “to collide with”

Colliding of the patient’s immune defenses with an invading pathogen…

Historical Perspective

Majno G. J Infect Dis. 1991;163:937-945.



Blood Pressure

BP = CO * SVR

SV * HR



Vasodilation, loss of vascular tone Hypoperfusion

Hypovolemic

Venodilation, capillary leak, vomiting, diarrhea, sweating Loss of cardiac filling pressures

Cardiogenic

TNF-α, interleukin-1β

Obstructive

In-situ thrombosis

Septic Shock is a Melting

Pot of Shocks!



Capillary refill time, skin mottling, cool extremities

Diminished skin turgor, dry axillae

Hypernatremia, elevated H/H

Tachycardia, arterial hypotension

Orthostatic hypotension

Increased serum lactate

Decreased renal perfusion

Low UOP, concentrated urine

Hypovolemia



Physical exam (PE) findings are non-sensitive and non-specific

Fluids and Catheters Treatment Trial (FACTT) post-hoc analysis

PE findings compared to PA catheter findings Not useful predictors of a low CI or low SvO2

Clinical Manifestations of

Hypovolemia

Grissom CK, et al. Crit Care Med. 2009;37:2720-2726.



Initial resuscitation within 6 hours of hypotension or elevated lactate >4 mmol/L (1C)

Resuscitation goals (1C)

Central venous pressure 8-12 mmHg

12-15 mmHg if mechanical ventilation or IAH present to account for cardiac filling impediments

Mean arterial pressure > 65 mmHg Higher if underlying hypertension

Urine output > 0.5 ml/kg/hr

Central venous (superior vena cava) oxygen saturation > 70% or mixed venous > 65% (5-7% lower than ScvO2)

Surviving Sepsis Campaign – 2008



Early goal-directed resuscitation improves survival

Reduced 28-day mortality rate from 46.5% to 30.5%

Crystalloid or colloids (1B)

Use a fluid challenge technique with evaluation (1D)

1,000ml crystalloid or 300-500ml colloid over 30-min More rapid or larger volumes may be required Reduce if cardiac filling pressures increase

If resuscitation goals NOTmet:

Transfuse PRBCs to Hct of > 30% (2C) and/or Dobutamine < 20 mcg/kg/min (2C)

SSC 2008 - Resuscitation

Dellinger RP, et al. Crit Care Med. 2008;36:296-327.



Normalize lactate levels ASAP if cannot monitor ScvO2

(2C)

Use crystalloid as the initialresuscitation fluid (1A)

Minimum of 30ml/kg in first 4-6 hours

For as long as there is evidence of fluid response (1C)

Add albumin to initial crystalloids (2B)

Recommend against the use of hydroxyethyl starches with MW > 200 Da or degree of substitution > 0.4 (1B)

Silent on the use of hetastarches of lower MW or gelatins pending results of ongoing trials

SSC 2012 - Resuscitation

R. Phillip Dillinger, M.D. – SCCM’s 41st_{Critical Care Congress.}



Crystalloids versus

Colloids



Na - 154 mmol/L Cl - 154 mmol/L

Volume expansion – 20% of administered volume

Duration of volume expansion – 30-60 minutes

May develop a hyperchloremic metabolic acidosis

Crystalloid – NaCl 0.9%



Osmolarity - 275 mOsm/L

Na - 130 mmol/L Cl - 110 mmol/L K - 4 mmol/L

Hypotonic – may exacerbate cerebral edema in TBI

Calcium - 3 mmol/L

Lactate – 28 mmol/L

May buffer acidemia

Volume expansion

Duration of volume expansion – 30-60 minutes

Crystalloid – Lactated Ringer’s



Dissolved in NaCl 0.9% or a balanced salt solution 4-5%

Osmolarity – 290 mOsm/L

Volume expansion = to volume administered Duration of volume expansion – 12-24 hours?

20-25%

Osmolarity – 310 mOsm/L

Volume expansion = 3-4X volume administered Draws volume from interstial space!!

Value of crystalloid therapy priorto use

Duration of volume expansion – 12-24 hours?

Monitor for allergic reactions



Effective volume expander Reduces TNF-α and augments IL-10

Restores proinflammatory/anti-inflammatory balance Hydroxyethylstarch

Synthetic colloid derived from amylopectin Can cause AKI, coagulopathy, reduced survival

Bayer O, et al. Crit Care Med. 2012;40:2543-2551. Perner A, et al. NEJM. 2012;367:124-134.

Other Fluids



Can cause AKI and anaphylactoid reactions

Gelatins

Produced from bovine collagen

Can cause AKI and anaphylactoid reactions Not available in the U.S.

Other Fluids



2-4X more volume of crystalloid is

required to achieve the same

endpoint as a colloid

So what?



Multi-center, randomized, double-blind trial

Compared albumin 4% to normal saline in a heterogeneous ICU population

Primary outcome was death during the 28-day period after randomization

Secondary outcomes included organ damage, duration of MV, CRRT, ICU or hospital LOS

No difference between both groups

SAFE Study

SAFE Study Investigators. NEJM. 2004;350:2247-2256.

Kaplan–Meier Estimates of the Probability of Survival.

Relative Risk of Death from Any Cause among All the Patients and among the Patients in the Six Predefined Subgroups.

The SAFE Study Investigators. N Engl J Med 2004;350:2247-2256.

Subset of patients with sepsis did better with albumin (NS, P=0.06) Significant increase in mortality with albumin in head trauma injury P = 0.009



Fluid overload has been associated with worse outcomes in patients with sepsis

Edema from increased capillary permeability Can lead to impaired organ function:

Pulmonary edema Congestive heart failure Impaired gut absorption

Increased abdominal pressures leading to IAH Most of the peripheral edema is cosmetic

Will resorb and be cleared over time

Negative Consequences

Rivers EP, et al. Curr Opin Crit Care. 2010;16:297-308.



Macrocirculation versus microcirculation

Assess BP, HR, UOP, skin perfusion

Lactate

Good marker but does serve as a real-time indicator

Achieve predetermined values

SSC Guidelines

Optimize systemic oxygen delivery (DO2)

How to assess fluid responsiveness??



Pulmonary artery occlusion pressure

Left ventricular end-diastolic volume

Measurements may not be reliable in states of pulmonary hypertension or LV/RV compliance changes

CO increases and stroke volume variation decreases may be a sign of resolving hypovolemia

Static Measures

Rivers EP, et al. Curr Opin Crit Care. 2010;16:297-308.



Pulse pressure variation (PPV) is defined as the difference between the maximal pulse pressure and the minimum pulse pressure divided by the average of these two parameters

Surrogate for stroke volume

A PPV of 10-15%during positive pressure breathing is highly sensitive and specific for determining CO responsiveness to changes in preload

Patient must be sedated

Dynamic Measures

Rivers EP, et al. Curr Opin Crit Care. 2010;16:297-308.



Passive leg raises can be used to assess volume status

“Reversible 200-300ml bolus”

Use of NICOM® (bioreactance) and carotid doppler Marik PE, et al. in Chest 2012 (published ahead of print)

Carotid doppler flow threshold of 20% found it useful assessment of predicting volume responsiveness Echocardiography may be used to assess cardiac output,

myocardial dysfunction, pericardial disease, pneumothoraces

Increased arterial-mixed venous carbon dioxide gradients or (a-v)CO2are seen in circulatory failure and inversely

correlate with cardiac index

Other Measurements or Indices



Inflammation Vasopressor use Corticosteroid use

Need for invasive monitoring (PA or arterial line catheterization)

Adequate Fluid Resuscitation May:



When fluid administration fails to

restore adequate arterial pressure

and organ perfusion

Initiate vasopressors



Activation of inducible NO synthase (iNOS) Directly and via cGMP to:

Lower intracellular calcium levels Decrease myosin light chain phophorylation Activate ATP-sensitive potassium channels Leads to:

Persistent vascular smooth muscle hyperpolarization

Decreased calcium entry

Hypotension

Hyporesponsiveness to catecholamines Adrenoreceptor desensitization

Pathogenesis of Vasodilatory Shock



Vasopressors



Norepinephrine or dopamine administered centrally are the initial vasopressors of choice (1C)

Epinephrine, vasopressin, phenylephrine are not initial vasopressors of choice (2C)

Vasopressin 0.03 units/min may be sequentially added to norepinephrine

Use epinephrine as the first alternative if not responsive to norepinephrine or dopamine

Do not use renal-dose dopamine (1A)

Insert an arterial line as soon as practical (1D)

Surviving Sepsis Campaign – 2008

Dellinger RP, et al. Crit Care Med. 2008;36:296-327.



Norepinephrine is the first vasopressor of choice

(1B)

Add or substitute epinephrine when an additional drug is required (2B)

Vasopressin 0.03 units/min may be added or substituted for norepinephrine (2A)

Dopamine is an alternative but ONLYin highly selected patients at very low risk of arrhythmias and with a low cardiac output/heart rate (1C)

Surviving Sepsis Campaign - 2012



Alpha-1 receptor agonist

Vasoconstriction

Beta-1 receptor agonist

Increased inotropy and chronotropy

Beta-2 receptor agonist

Peripheral vasodilation

Vasoconstriction potency

Epinephrine > norepinephrine > dopamine > phenylephrine

Chronotropy potency

Epinephrine > dopamine > norepinephrine

Pharmacology 101



Onset/duration: very rapid/1-2 minutes

Metabolized by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO)

Dose: 0.01-3.3 mcg/kg/min

Dilute with dextrose solution

Administer through large central veins

Adverse effects

Ischemic injury, tachycardia, bradycardia, agitation

Norepinephrine



Alpha-1, beta-1, and dopamine receptor agonist

Dose-dependent effect

Onset/duration: 2-5 minutes/10 minutes Metabolized by COMT and MAO

25% metabolized to norepinephrine

Dose: 5-20 mcg/kg/min

Administer through large central veins Adverse effects

Ischemic injury, dysrhythmias, hypoprolactinemia, hallucinations, agitation, reduced growth hormone levels



V1A/V1B (V3) – vasoconstriction

V2 – renal tubule aquaporin insertion and water reabsorption

Onset/duration: 5 minutes/20 minutes

Metabolized by hepatic and renal vasopressinases

Dose: 0.01-0.04 units/min

Physiologic or replacement dosing? Titrate or fixed dose?

Higher doses (0.067 units/min)? Early versus late administration?

Vasopressin (ADH)



Administer through large central veins

Adverse effects

Ischemic injury, chest pain, dysrhythmias, water intoxication, decreased cardiac output

Vasopressin (ADH)



Found on arterial, splanchnic, renal, coronary vascular beds

Coupled through Gq/11to phospholipase C and

activates protein kinase C Elevates intracellular calcium

May sensitize the contractile apparatus to calcium Mediates closureof ATP-sensitive potassium channels

Vasopressin Pharmacology



Mediate the ADH effect

Coupled through Gsto adenylyl cyclase increasing

cAMP, activates protein kinase A, and the insertion of aquaporins into the luminal membranes of the renal collecting ducts

V1B (V3) receptors

Found in anterior pituitary Activates secretion of ACTH

Increases cortisol secretion

Increases adrenoreceptor gene expression and may restore vascular sensitivity

Vasopressin Pharmacology



Vasopressin Pharmacology

Addresses the pathophysiology of

septic shock and re-sensitizes to the

effect of catecholamines!!



Onset/duration: very rapid/10-20 minutes

Metabolized by hepatic deamination, glucuronidation, and sulfation

Doses: 25-800 mcg/min

Bolus doses of 100 mcg

Adverse effects

Ischemic injury, reflex bradycardia, chest pain

Phenylephrine



Alpha-1, beta-1, beta-2 receptor agonist

Dose-dependent effect

Onset/duration: very rapid/5-10 minutes

Metabolized by COMT and MAO

Doses: > 0.05 mcg/kg/min

Adverse effects

Ischemic injury, chest pain, dysrhythmias, hyperglycemia

Increased lactate levels (type A and type B)

Epinephrine

www.paduiblog.com



1,058 patients with shock

462 (14.7%) had septic shock 375 (35.4%) received dopamine 683 (64.6%) received another vasopressor

Dopamine group:

Higher ICU mortality: 42.9% vs. 35.7%, p=0.02 Higher hospital mortality: 49.9% vs. 41.7%, p=0.01 In multivariate analysis, dopamine administration

independent risk factor for ICU mortality

Sepsis Occurrence in Acutely Ill

Patients (SOAP I)



Multi-center randomized trial Methods

Target MAP determined by MD

Dopamine (N=858) maximum dose – 20 mcg/kg/min Norepinephrine (N=821) max dose – 0.19 mcg/kg/min Open-label norepinephrine may be added

Epinephrine and vasopressin may be added as rescue Rx Primary endpoint was death at 28-days

Secondary endpoints were death in the ICU/hospital, LOS, # days without organ support, ADEs.

Dopamine versus Norepinephrine in

the Treatment of Shock (SOAP II)

DeBacker D, et al. NEJM. 2010;362:779-789.



Septic-62.2%, cardiogenic-16.7%, hypovolemic-15.7%

Similar use of fluids, APC, corticosteroids, epinephrine, vasopressin

More patients in dopamine group required norepinephrine (26% versus 20%, p<0.001)

More patients in the dopamine group had an arrhythmia (24.1% versus 12.4%, p<0.001)

Atrial fibrillation occurred 86.1%

Discontinuation rate higher in dopamine group (6.1% versus 1.6%, p<0.001)

SOAP II

DeBacker D, et al. NEJM. 2010;362:779-789.

Kaplan–Meier Curves for 28-Day Survival in the Intention-to-Treat Population.



Death from refractory shock occurred more frequently in the dopamine group (46% versus 41%p=0.05)

Rate of death at 28-days was significantly higher among cardiogenic shock patients treated with dopamine (p=0.03)

Cause unknown

Ischemic events?

SOAP II

DeBacker D, et al. NEJM. 2010;362:779-789.



Dopamine-resistant patients (20 mcg/kg/min) Excluded if ischemic, CHF, PE, arrhythmias

Dobutamine was administered first

Brief dopamine was started if hypotension developed until group randomization

Norepinephrine (N=15) or epinephrine (N=15) was added according to the randomization code

Initial dose for both drugs: 0.1 mcg/kg/min Dobutamine was stopped in the epinephrine group

Norepinephrine-Dobutamine versus

Epinephrine in Cardiogenic Shock

Levy B, et al. Crit Care Med. 2011;39:450-455.

Levy B, et al. Crit Care Med. 2011;39:450‐455. 2 Evolution of mean arterial pressure (MAP) 

(top), cardiac index (CI) (middle), and heart 

rate (HR) (bottom). 

Squares, epinephrine‐treated patients; 

triangles, norepinephrine‐dobutamine‐treated 

patients.

Heart rate significantly higher in the 

Levy B, et al. Crit Care Med. 2011;39:450‐455. 2 Evolution of lactate (top), PCO2 gap (middle), 

and diuresis (bottom). 

Squares, epinephrine‐treated patients; triangles, 

norepinephrine‐dobutamine‐treated patients. Epinephrine group had a higher lactate level in 

the first 12 hours (p<0.05) and a higher PCO2 

gap (p<0.01).

Norepinephrine‐dobutamine had a greater 

effect on diuresis (no difference in SCr).



Multi-center, double-blind randomized trial

Norepinephrine-dobutamine (N=169) – 0.2 mcg/kg/min plus 5 mcg/kg/min

Epinephrine (N=161) – 0.2 mcg/kg/min

Target MAP > 70 mm Hg

Primary endpoint was 28-day mortality

Secondary endpoints were 90-day survival, ICU/hospital discharge, hemodynamics, lactate

Norepinephrine-Dobutamine versus

Epinephrine in Septic Shock

Annane, D, et al. Lancet. 2007;370:676-684.

Survival from randomization to day 90 No difference in mortality rates, p=0.31

Annane, D, et al. Lancet. 2007;370:676-684. -No difference in MAP attainment

-Significantly lower arterial pH in the epinephrine group on day 1 (p<0.001) day 2 (p=0.0008), day 3 (p=0.0019, and day 4 (p=0.0007)

-Arterial lactate was significantly higher in the epinephrine group on day 1 (p=0.0003)

-No difference other measured parameters or ADEs



Multi-center, randomized, double-blind trial

Addition to open-label catecholamines adjusted to MAP between 65-70 mm Hg if not achieved by study drug

Vasopressin (N=396) – started at 0.01 units/min and titrated up to 0.03 units/min

Norepinephrine (N=382) – started at 5 mcg/min and titrated up to 15 mcg/min

Stratum of less severe shock defined as norepinephrine doses between 5-14 mcg/min

Exclusion criteria – ACS, low cardiac output states Plasma was collected in a subgroup of patients (N=107)

for measurement of vasopressin levels

Vasopressin and Septic Shock

Trial (VASST)

Russell JA, et al. NEJM. 2008;358:877-887.



Primary outcome was 28-day mortality

Secondary outcomes were 90-day mortality, free from organ dysfunction/vasopressor use/MV/CRRT/SIRS/corticosteroid use, LOS in the ICU and hospital

Results (vasopressin versus norepinephrine)

No difference in 28-day mortality (35.4% versus 39.3%, p=0.26) No difference in 90-day mortality (43.9% versus 49.6%, p=0.11) No difference in other secondary outcomes

No difference in serious ADEs (10.3% versus 10.5%, p=1.00) Rate of norepinephrine use was lower in the vasopressin group

during the first 4 days (p<0.001)

VASST

Russell JA, et al. NEJM. 2008;358:877-887.



Plasma vasopressin levels

Low at baseline – median: 3.2 pmol/L (1.7-4.9) Levels did not change in the norepinephrine group In the vasopressin group:

Median at 6 hours: 73.6 pmol/L (58.6-94.7)

Median at 24 hours: 98.0 pmol/L (67.1-127.8)

In patients with less severe shock, there were trends in favor of vasopressin group at both 28-day (26.5% versus 35.7%, p=0.05) and 90-day mortality (35.8% versus 46.1%, p=0.04)

Significance not known!

Post-hoc analyses favored vasopressin – low lactate levels, one vasopressor use, at risk for AKI, concomitant corticosteroid use

VASST

Russell JA, et al. NEJM. 2008;358:877-887. Bauer S, et al. Pharmacotherapy. 2010;30:1057-1071.



Phenylephrine Data?



Use dobutamine in patients with myocardial dysfunction as supported by elevated cardiac filling pressures and low cardiac output (1C)

Do not increase cardiac index to predetermined supranormal levels (1B)

No mention of milrinone

SSC 2008 – Inotropes

Dellinger RP, et al. Crit Care Med. 2008;36:296-327.



Dobutamine can be started or added to a vasopressor in myocardial dysfunction or ongoing evidence of hypoperfusion, even after adequate intravascular volume and MAP are achieved (1C)

No mention of milrinone

SSC 2012 – Inotropes

R. Phillip Dillinger, M.D. – SCCM’s 41st_{Critical Care Congress.}



D-isomer: beta-1 and beta-2 agonist

L-isomer: beta-1 agonist and weak alpha-1 agonist

Onset/duration: 2-10 minutes/10 minutes

Metabolized by COMT and MAO

Dose: 2.5-20 mcg/kg/min

Adverse effects

Dysrhythmias, ventricular ectopy, chest pain

Dobutamine



Increases intracellular calcium and myocardial contractility independent of beta-1 receptors

Onset/duration: 5-15 minutes/10+ hours

Metabolized by glucuronidation (15%)

Eliminated renally

Dose: 0.25-0.5 mcg/kg/min

Adverse effects

Ventricular ectopy, hypotension, thrombocytopenia

Milrinone



Hyporesponsiveness to catecholamines

TNF-α and IL-βmediate uncoupling of beta-1 receptors and impair influx of calcium into myocytes Apoptosis?

Makes pharmacologic sense to use milrinone

One small trial of 12 pediatric patients

Increased cardiac index in patients with sepsis and concomitant catecholamines

Barton P, et al. Chest. 1996;109:1302-1312.

Myocardial Depression in Sepsis



70-year old male (5’10” 80kg) presents to the MICU from the cardiac rehabilitation unit

VS: BP- 80/30 (via BP cuff) 120 ST 22 103° F Labs pending

Witnessed aspiration

What is your hemodynamic management strategy?

Choice of fluids and rate? Pharmacologic support? Goals of resuscitation?



Macrocirculation and microcirculation-specific goals are important to define and achieve in order to restore effective tissue perfusion and normalize cellular metabolism

Early titrated fluid administration improves microvascular perfusion and improves outcome

The type of fluid solution does not seem to influence goal attainment, however, isotonic crystalloid solutionsmay be preferred as initial resuscitative fluid support

Summary and Conclusion



Norepinephrinemay be the preferred initial agent for the management of septic shock

Vasopressin may have an important adjunctive role in the management of septic shock

Consider early administration

Summary and Conclusion